The SARS-CoV-2 receptor, angiotensin-converting enzyme 2, is required for human endometrial stromal cell decidualization†

Biol Reprod. 2021 Feb 11;104(2):336-343. doi: 10.1093/biolre/ioaa211.


The coronavirus disease 2019 (COVID-19) first appeared in December 2019 and rapidly spread throughout the world. The SARS-CoV-2 virus enters the host cells by binding to the angiotensin-converting enzyme 2 (ACE2). Although much of the focus is on respiratory symptoms, recent reports suggest that SARS-CoV-2 can cause pregnancy complications such as pre-term birth and miscarriages; and women with COVID-19 have had maternal vascular malperfusion and decidual arteriopathy in their placentas. Here, we report that the ACE2 protein is expressed in both endometrial epithelial and stromal cells in the proliferative phase of the menstrual cycle, and the expression increases in stromal cells in the secretory phase. It was observed that the ACE2 mRNA and protein abundance increased during primary human endometrial stromal cell (HESC) decidualization. Furthermore, HESCs transfected with ACE2-targeting siRNA impaired the full decidualization response, as evidenced by a lack of morphology change and lower expression of the decidualization markers PRL and IGFBP1. Additionally, in mice during pregnancy, the ACE2 protein was expressed in the uterine epithelial cells, and stromal cells increased through day 6 of pregnancy. Finally, progesterone induced Ace2 mRNA expression in mouse uteri more than vehicle or estrogen. These data establish a role for ACE2 in endometrial physiology, suggesting that SARS-CoV-2 may be able to enter endometrial stromal cells and elicit pathological manifestations in women with COVID-19, including an increased risk of early pregnancy loss.

Keywords: ACE2; SARS-CoV-2; decidualization; endometrium; stromal cells.

MeSH terms

  • Angiotensin-Converting Enzyme 2 / genetics
  • Angiotensin-Converting Enzyme 2 / metabolism*
  • Animals
  • COVID-19 / complications
  • COVID-19 / virology*
  • Cells, Cultured
  • Endometrium / cytology
  • Endometrium / physiology*
  • Female
  • Gene Expression Regulation, Enzymologic / physiology
  • Gene Knockdown Techniques
  • Humans
  • Insulin-Like Growth Factor Binding Protein 1 / genetics
  • Insulin-Like Growth Factor Binding Protein 1 / metabolism
  • Mice
  • Pregnancy
  • Prolactin / genetics
  • Prolactin / metabolism
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • SARS-CoV-2 / physiology*
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism
  • Stromal Cells / physiology*


  • IGFBP1 protein, human
  • Insulin-Like Growth Factor Binding Protein 1
  • RNA, Messenger
  • Prolactin
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2
  • Serine Endopeptidases
  • TMPRSS2 protein, human